Herpes simplex virus (HSV) has a virulence determining locus in the long repeat region of its genome (Ackermann et al., 1986; Chou and Roizman, 1990; McGeoch et al., 1991; Dolan et al., 1992). The virulence phenotype has been specifically assigned to the RL1 gene and its encoded protein ICP34.5 (McKie et al., 1994). Null mutants in ICP34.5 are totally avirulent in mice (Taha et al., 1989a, b; Chou et al., 1990; MacLean et al., 1991) and the function of the protein in vitro has been shown to be cell type and cell state specific, depending on the stage in the cell cycle and the differentiation state (Brown et al., 1994).
One ICP34.5 function demonstrated in a human neuroblastoma cell line is the preclusion of host cell protein synthesis shut-off via the protein kinase PKR pathway following HSV infection (Chou and Roizman, 1992; Chou et al., 1995). This response to expression of ICP34.5 is however not ubiquitous and the precise molecular functions of ICP34.5 remain unknown.
A 63 amino acid carboxy terminal domain of ICP34.5 has been shown to share significant homology (McGeoch and Barnett, 1991) with the carboxy domain of the mouse myeloid differentiation protein MyD116 (Lord et al., 1990) and the hamster growth arrest and DNA damage gene GADD34 (Fornace et al., 1989) although the amino terminal parts of the proteins are quite diverse. The role of MyD116 and GADD34 in the cell appears to be in blocking growth and DNA replication following damage and thus they may act as tumour suppressor genes. The HSV type 1 (HSV1) strain 17 ICP34.5 protein comprises 248 amino acids whereas MyD116 and GADD34 are 657 and 590 amino acids respectively. Chou and Roizman (1994) have demonstrated that the carboxy terminus 63 amino acids are essential but not necessarily sufficient for the host cell shut-off phenotype of ICP34.5 and can be replaced by the homologous domain of